Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) is a free radical scavenger. We tested the hypothesis that combination treatment of Edaravone and recombinant tissue plasminogen activator (tPA) extends the therapeutic time window. Male Wistar rats were subjected to 1.5-, 3.0- or 4.5-hour middle cerebral artery (MCA) occlusion (MCAO) by a nylon thread. Animals were randomly divided into four groups. The Sham group rats were operated without MCAO and drug injection. In the Vehicle-treated group the same volume of saline was given every 1.5 hours from just after MCAO to just before reperfusion. In the Vehicle + tPA-treated group saline injection was given as above and tPA (5 mg/kg, i.v.) was given once just after reperfusion. Edaravone+tPA-treated group: Edaravone (3 mg/kg, i.v.) was given every 1.5 hours instead of saline and tPA injection as above. Survival rate, infarct size and evidence of apoptosis and hemorrhage were examined in the animals. Combining administration of Edaravone+tPA significantly increased survival rate after 3 hours of transient MCAO, and reduced infarct volume after 1.5 hours of transient MCAO compared with the vehicle or vehicle+tPA groups. In Edaravone+tPA-treated group, the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) and 4-hydroxynonenal (4-HNE) positive cells were reduced at 16 hours after 3 hours of transient MCAO, but not in advanced glycation end products (AGEs) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Hemorrhage rate and the area decreased in the Edaravone+tPA-treated group. The combination therapy of Edaravone+tPA increased survival rate, and reduced the infarct volume and hemorrhage with reduction of lipid peroxidation. Therefore, Edaravone combination is expected to extend the therapeutic time window of tPA in the clinical situation.
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PMID:Extension of ischemic therapeutic time window by a free radical scavenger, Edaravone, reperfused with tPA in rat brain. 1514 31

Free radicals are known to activate coagulation and inhibit fibrinolysis. Edaravone, a free radical scavenger, protects vascular endothelial cells and neurons during acute brain ischemia in in vitro models. Hemorrhagic transformation and treatment outcomes were retrospectively examined in 76 patients with acute cardiogenic embolism treated with edaravone in addition to routine treatment within 24 hours of the onset of symptoms. Hemorrhagic transformation was categorized according to European Cooperative Acute Stroke Study-II. Patient characteristics were also evaluated, including evidence of hypertension, diabetes mellitus, hyperlipidemia, coronary heart disease, history of smoking, National Institutes of Health Stroke Scale on arrival, and modified Rankin scale at 3 months post-onset. Edaravone administration was one of the factors that contributed to increased frequency of hemorrhagic transformation, but had showed no significant relationship with the outcome. The present study showed that edaravone administration increased the frequency of hemorrhagic transformation with heparin in patients with cardiogenic embolism. Free radical scavenging may have promoted the coagulating conditions. Edaravone administration may allow reduction of the dose of heparin and tissue plasminogen activator in patients with acute ischemic stroke.
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PMID:Administration of free radical scavenger edaravone associated with higher frequency of hemorrhagic transformation in patients with cardiogenic embolism. 1865 47

Edaravone is a lipophilic drug with multiple mechanisms of action. Because edaravone is a promising drug candidate for the treatment of stroke, we tested the hypothesis that edaravone would be neuroprotective following cerebral ischemia using a rabbit embolic stroke model with a well-defined behavioral endpoint. Using the rabbit small clot embolic stroke model (RSCEM), a drug or drug combination is considered beneficial if it significantly increases the amount of microclots (mg) measured in brain that produce neurologic dysfunction in 50% of a group of animals (P(50)) compared to the control group. Edaravone (100 mg/kg, s.c.), increased the P(50) value to 1.80+/-0.24 mg (p<0.05) when administered 5 min following embolization and increased P(50) values by 195% and 161% (compared to control) when administered 1 and 3 h following embolization, respectively, but was inactive when applied 6 h following embolization, compared to the cumulative control group (P(50)=0.93+/-0.16 mg). To simulate the design of current clinical trials, edaravone was also given following a standard tPA regimen, which by itself increased the P(50) value to 2.72+/-0.28 mg. When tPA was infused 1 h following embolization and edaravone was given 3 h following embolization, the P(50) was 2.68+/-0.56 mg. This study indicates that edaravone may have substantial therapeutic benefit for the treatment of AIS since it had a therapeutic widow of at least 3 h in rabbits. Edaravone can also be administered with a thrombolytic to improve behavior.
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PMID:The lipophilic multifunctional antioxidant edaravone (radicut) improves behavior following embolic strokes in rabbits: a combination therapy study with tissue plasminogen activator. 1885 64

A free radical scavenger Edaravone is the first clinical drug for neuroprotection in the world which has been used from 2001 in most ischemic stroke patients in Japan, and is especially useful in thrombolytic therapy with tissue plasminogen activator (tPA). Of great importance for regenerative therapy and gene therapy are the neural stem cells which are intrinsically activated or exogenously transplanted. Addition of NTFs greatly enhanced an intrinsic migration or invasion of stem cells into the scaffold, which could provide a future regenerative potential against ischemic brain damage at chronic stage.
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PMID:[Neuroprotective therapy for ischemic stroke with free radical scavenger and gene-stem cell therapy]. 1919 9

Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) after ischemic stroke is effective. However, rtPA potentiates neuronal damage, and interactions between rtPA and thrombolysis products (TLP) have been reported to play a role in this. In the present study we investigated the mechanisms underlying rtPA- and TLP-induced neurotoxicity. Adult male Sprague-Dawley rats were subjected to 60-min intraluminal middle cerebral artery (MCA) occlusion, and then treated with rtPA (10 mg/kg), TLP, or saline. To evaluate the effects of a free radical scavenger, treatment with edaravone and TLP was evaluated. To investigate the role of red blood cells (RBCs), RBC-depleted TLP was used. Neurological deficit scores, infarct volume, and immuno-histochemical localization of oxidative end products for lipid and DNA (4-hydroxy-2-nonenal [4-HNE] and 8-hydroxy-deoxyguanosine [8-OHdG]) were evaluated. TLP increased the infarct volume, worsened the neurological deficits, and increased accumulations of 4-HNE and 8-OHdG. Edaravone treatment significantly reduced the lesion volume and improved the neurological score. Both infarct volume and accumulation of oxidative products were significantly suppressed when RBC-depleted TLP was used. In this mechanical model of MCA occlusion, rtPA-induced TLP, especially in the presence of RBCs, contributed to neuronal damage by accelerating free radical injury.
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PMID:Mechanistic insight into neurotoxicity of tissue plasminogen activator-induced thrombolysis products in a rat intraluminal middle cerebral artery occlusion model. 1927 67

Acute stroke, including acute ischemic stroke (AIS) and acute hemorrhagic stroke, (AHS) is a common medical problem with particular relevance to the demographic changes in industrialized societies. In recent years, treatments for AIS have emerged, including thrombolysis with tissue plasminogen activator (t-PA). Although t-PA is the most effective currently available therapy, it is limited by a narrow therapeutic time window and side effects, and only 3% of all AIS patients receive thrombolysis. Edaravone was originally developed as a potent free radical scavenger and, since 2001, has been widely used to treat AIS in Japan. It was shown that edaravone extended the narrow therapeutic time window of t-PA in rats. The therapeutic time window is very important for the treatment of AIS, and early edaravone treatment is more effective. Thus, more AIS patients might be rescued by administering edaravone with t-PA. Meanwhile, edaravone attenuates AHS-induced brain edema, neurologic deficits and oxidative injury in rats. Although edaravone treatment is currently only indicated for AIS, it does offer neuroprotective effects against AHS in rats. Therefore, we hypothesize that early administration of edaravone can rescue AHS patients as well as AIS patients. Taken together, our findings suggest that edaravone should be immediately administered on suspicion of acute stroke, including AIS and AHS.
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PMID:Edaravone: a new therapeutic approach for the treatment of acute stroke. 2072 80

Possible strategies for treating stroke include: 1) thrombolytic therapy with tissue plasminogen activator (tPA): restoring cerebral blood flow in the acute phase of ischemic stroke but sometimes causing hemorrhagic transformation (HT); 2) stem cell therapy: the repair of disrupted neuronal networks with newly born neurons in the chronic phase of ischemic stroke. Firstly, we estimated the vascular protective effect of a free radical scavenger, edaravone, in the tPA-treated rat model of middle cerebral artery occlusion. Edaravone prevented dramatically decreased the hemorrhagic transformation and improved the neurologic score and survival rate of tPA-treated rats. Secondly, we attempted to restore brain tissue using a novel biomaterial, polydimethysiloxane-tetraethoxysilane (PDMS-TEOS) hybrid with or without vascular endothelial growth factor (VEGF), and we could show that implantation of a PDMS-TEOS scaffold with VEGF might be effective for treating old brain infarction or trauma. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes.
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PMID:Vascular protection and restorative therapy in ischemic stroke. 2088 80

Stroke is an enormous public health problem with an imperative need for more effective therapy. Recombinant tissue plasminogen activator is the only licensed drug for acute stroke, but its efficacy may be limited by the toxicity of the compound and by reperfusion injury. The coadministration of neuroprotective drugs could augment the value of thrombolytic therapy, but the evidence in support of this approach is scarce. The use of the free radical trapping NXY-059, either with or without recombinant tissue plasminogen activator, was not successful in Phase III studies. However, these results could reflect its weak antioxidant capacity, poor blood-brain barrier penetration, and lack of synergism with recombinant tissue plasminogen activator as well as the overly broad treatment window used in the reported trials. This article contends that further translational research should explore newer antioxidant drugs in combination with thrombolytic agents, but only if the combination yields additive or synergistic effects in preclinical thromboembolic models or in biomarker-assisted Phase II studies. Edaravone and novel nitrones endowed with a better pharmacokinetic profile or multitarget and thrombolytic activity are discussed as well as the latest research data on uric acid, a strong endogenous antioxidant in blood that is early consumed after acute stroke. The coadministration of uric acid and recombinant tissue plasminogen activator has shown to provide synergistic neuroprotection in experimental thromboembolic models and to lessen several biomarkers of oxidative stress in patients with acute stroke. The clinical efficacy of uric acid is currently under investigation in a Phase III trial that follows current recommendations of also evaluating surrogate biomarkers of treatment effects.
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PMID:Translational stroke research of the combination of thrombolysis and antioxidant therapy. 2181 42

Neuroprotection is essential for therapy in acute stage of stroke. Both neurotrophic factors (NTFs) and free radical scavenger can be such neuroprotective reagents with inhibiting death signals and potentiating survival signals under cerebral ischemia. Edaravone, a free radical scavenger, is the first clinical drug for neuroprotection in the world which has been used from 2001 in most ischemic stroke patients in Japan. Edaravone scavenges hydroxyl radicals both in hydrophilic and hydrophobic conditions, and is especially useful in thrombolytic therapy with tissue plasminogen activator (tPA). Combination therapy of Edaravone with tPA greatly increased survival of stroke animals, reduced infarct size, and inhibited molecular markers of oxidative damage in lipid, protein and DNA. Use of Edaravone greatly reduced hemorrhagic transformation accompanied by tPA treatment, and may also extend therapeutic time window with tPA therapy for more than 3 hr in human stroke patients.
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PMID:[Therapeutic time window for ischemic stroke]. 2227 27

Acute ischemic stroke (AIS) is a major cause of morbidity and mortality in the aging population worldwide. Alteplase, a recombinant tissue plasminogen activator, is the only Food and Drug Administration-approved thrombolytic agent for the treatment of AIS. Only 2-5% of patients with stroke receive thrombolytic treatment, mainly due to delay in reaching the hospital. Edaravone is a free radical scavenger marketed in Japan to treat patients with AIS, who present within 24 h of the onset of symptoms. When used in combination with alteplase, edaravone may have three useful effects: enhancement of early recanalization, inhibition of alteplase-induced hemorrhagic transformation and extension of the therapeutic time window for alteplase. This is the first review of the literature evaluating the clinical efficacy of edaravone, aiming to clarify whether edaravone should be further evaluated for clinical use worldwide. This review covers both clinical and experimental studies conducted between 1994 and 2012. Edaravone is a potentially useful neurovascular protective agent, used in combination with thrombolytic agents to treat >15 million patients devastated by stroke worldwide annually. Additional clinical studies are necessary to verify the efficacy of edaravone when used in combination with a thrombolytic agent.
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PMID:Edaravone (Radicut), a free radical scavenger, is a potentially useful addition to thrombolytic therapy in patients with acute ischemic stroke. 2464 84


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